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1 Department of Physiology and Biophysics, Case Western Reserve University, School of Medicine, Cleveland, OH, USA
2 Department of Medicine, Case Western Reserve University, School of Medicine, Cleveland, OH, USA
3 Department of Physiology and Biophysics, Case Western Reserve University, School of Medicine, Cleveland, OH, USA; Department of Medicine, Case Western Reserve University, School of Medicine, Cleveland, OH, USA; Department of Medicine, Louis Stokes Veterans Administration Medical Center, Cleveland, OH, USA
4 Department of Physiology and Biophysics, Case Western Reserve University, School of Medicine, Cleveland, OH, USA; Department of Medicine, Case Western Reserve University, School of Medicine, Cleveland, OH, USA; Rammelkamp Center for Research and Education, MetroHealth System Campus, Kidney Disease Research Center, Cleveland, OH, USA
* To whom correspondence should be addressed. E-mail: john.sedor{at}case.edu.
Podocyte differentiation is required for normal glomerular filtration barrier function and is regulated by the transcription factor WT1. We identified WT1 Interacting Protein (WTIP) and hypothesized it functions both as a scaffold for slit diaphragm proteins and a co-repressor of WT1 transcriptional activity by shuttling from cell-cell junctions to nucleus after injury. Endogenous WTIP co-localizes with ZO-1 in cultured mouse podocyte adherens junctions. To model podocyte injury in vitro, differentiated podocytes were incubated with puromycin aminonucleoside (PAN, 100 µg/ml) for 24 h, which disassembled cell-cell contacts, rearranged actin cytoskeleton, and caused process retraction. Podocyte synaptopodin expression diminished after PAN treatment, consistent with podocyte dedifferentiation in some human glomerular diseases. To assess podocyte function, we measured albumin flux across differentiated podocytes cultured on collagen-coated Transwell filters. Albumin transit across PAN-treated cells increased to levels observed with undifferentiated podocytes. Consistent with our hypothesis, WTIP, as well as ZO-1, translocated from podocyte adherens junctions to nuclei in PAN-treated cells. Since WTIP is a transcriptional co-repressor for WT1, we examined the effect of PAN on expression of Rbbp7 (also known as RbAp46), a WT1 target gene expressed in S-shape bodies during nephrogenesis. Rbbp7 expression in PAN-treated podocytes was reduced compared to untreated cells. In conclusion, WTIP translocates from cell-cell junctions to the nucleus in PAN-treated podocytes. We suggest WTIP monitors slit diaphragm protein assembly and shuttles into the nucleus after podocyte injury, translating changes in slit diaphragm structure into altered gene expression and a less differentiated phenotype.
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